Weiteres

Login für Redakteure

Overview

The Anfinsen concept, that the one-dimensional primary polypeptide sequence holds the key to the three dimensional structure and thereby activity of a protein, is a fundamental tenet of modern biochemistry. The translation of the DNA-encoded sequence into a correctly folded polypeptide chain is essential for the vitality of the cell. Over the past decade, molecular chaperones and other enzymes have been identified that uphold this crucial activity. Even a partial breakdown in the control of protein folding can have disastrous effects, as witnessed by the debilitating neurodegenerative disorders, Morbus Alzheimer and Creutzfeld-Jakob disease. Yet there is an increasing body of evidence that the primary structure in itself is insufficient to define the precise three dimensional arrangement of the resulting protein product. This is because the thermodynamic energy profile of a folded protein exhibits a number of possible minima, with low energetic barriers between them. Nature has allowed some polypeptide sequences to adopt alternative folding patterns, resulting in differing functional species. This is particularly important if the function of a single polypeptide requires a response to changing molecular environments. Such dynamic responses have been observed upon protein interactions with representatives of the three major biological macromolecular classes: lipid membranes, nucleic acids and proteins. Recent examples from the literature include the anthrax toxin protective antigen , which undergoes a folding rearrangement upon binding to target membranes to form a conduit for lethal and oedema factors, the T7 RNA polymerase , where the transition from initiation to elongation is accompanied by a major refolding of some 300 amino terminal residues, or the thermosome , in which a alpha-strand in isolated beta-subunits shows a transition to alpha-helix to form the substrate-accepting chaperonin through complex formation with the alpha-subunit. The goal of GRK 1026 is to understand the relationship between folding transitions and biological action. Protein folding from the denatured state, both in vitro and enzymatically controlled, is a focal point in Halle. Building on this expertise, twelve scientists have decided to join forces to investigate the roles of folding transitions in macromolecular interactions. Making up thirteen groups from the departments of Biochemistry/Biotechnology, Biology, Chemistry, Pharmacy and Physics, as well as the Max-Planck-Forschungsstelle für Enzymologie der Proteinfaltung, we seek to examine the effects of such transitions on protein-lipid, protein-nucleic acid and protein-protein interactions at a biophysical, biochemical and cell biological level, under the integrative auspices of a Graduiertenkolleg.